Alzheimer's disease (AD) is the prototypic cortical dementia characterized by memory deficit together with dysphasia (language disorder in which there is an impairment of speech and of comprehension of speech), dyspraxia (disability to coordinate and perform certain purposeful movements and gestures in the absence of motor or sensory impairments) and agnosia (inability to recognize objects, persons, sounds, shapes, or smells) attributable to involvement of the cortical association areas. Special symptoms such as spastic paraparesis (weakness affecting the lower extremities) can also be involved [1-4].
Incidence of AD increases dramatically with the age. AD is at present the most common cause of dementia. It is clinically characterized by a global decline of cognitive function that progresses slowly and leaves end-stage patients bound to bed, incontinent and dependent on custodial care. Death occurs, on average, 9 years after diagnosis [5]. United Nations population projections estimate that the number of people older than 80 years will approach 370 million by the year 2050. Currently, it is estimated that 50% of people older than age 85 years are afflicted with AD. Therefore, more than 100 million people worldwide will suffer from dementia in 50 years. The vast number of people requiring constant care and other services will severely affect medical, monetary and human resources [6].
Memory impairment is the early feature of the disease and involves episodic memory (memory for day-to-day events). Semantic memory (memory for verbal and visual meanings) is involved later in the disease. By contrast, working memory (short-term memory involving structures and processes used for temporarily storing and manipulating information) and procedural memory (unconscious memory that is long-term memory of skills and procedure) are preserved until late. As the disease progresses, the additional features of language impairment, visual perceptual and spatial deficits, agnosias and apraxias emerge.
The classic picture of AD is sufficiently characteristic to allow identification in approximately 80% of cases [7]. Nevertheless, clinical heterogeneity does occur which is important for clinical management but also provides further implication of specific medication treatments for functionally different forms [8].
The pathological hallmarks of AD include deposition of extracellular amyloid plaques containing beta-amyloid peptides (Abeta), intracellular neurofibrillary tangles mainly composed of Tau protein and progressive neuronal and synaptic dysfunction and loss [9-11]. The etiology of Alzheimer's disease (AD) remains elusive, and for the last decades, several main hypotheses on the cause of AD have been proposed: the “cholinergic hypothesis” attributing a particular role for decreased acetylcholinergic signaling in development of AD, the “amyloid cascade hypothesis”, which states that the neurodegenerative process is a series of events provoked by the abnormal processing of the Amyloid Precursor Protein (APP) [12], the revised “Tau hypothesis” [13], which proposes that cytoskeletal changes are the triggering pathological events, and recently, neuroimmunomodulation hypothesis prioritizing changes in immune signaling in AD etiology and progression [19]. The most widely accepted theory explaining AD progression remains the amyloid cascade hypothesis [14-16] and AD researchers have mainly focused on determining the mechanisms underlying the toxicity associated with amyloidogenic Abeta peptides. Importantly, changes in microvascular permeability and vessels remodeling, manifested as aberrant angiogenesis and blood brain barrier breakdown in course of AD, have been identified as key events implicated to the APP toxicity [17].
Synaptic density change is a pathological lesion that correlates better with cognitive impairment than the depositions of APP and Tau aggregates. Studies have revealed that the amyloid pathology appears to progress in a neurotransmitter-specific manner where the cholinergic terminals appear most vulnerable, followed by the glutamatergic terminals and finally by the GABAergic terminals [11]. Glutamate is the most abundant excitatory neurotransmitter in the mammalian nervous system, and its functional effects are finely contra-balanced by GABAergic inhibitory neuronal receptors. Under pathological conditions, abnormal accumulation of glutamate in the synaptic cleft leads to glutamate receptors overactivation [18], that results in cognitive dysfunction and finally in neuronal cell death. This process, named excitotoxicity, is commonly observed in neuronal tissues during acute and chronic neurological disorders and is recognized now as one of the major pathological triggers in AD. Moreover, dysfunction in inhibitory GABA-mediated neuronal circuits observed in AD could increase negative consequences of dysregulated glutamate signaling in neuronal cells.
Up to now, two kinds of medications, accounting for only five drugs approved in most countries, are used for improving or slowing down symptoms of AD which lay on some acetylcholinesterase modulators and a blocker of NMDA glutamate Receptors (NMDAR) [20-22].
Acetylcholinesterase inhibitors such as donepezil, rivastigmine, tacrine and galantamine are currently available in the market and are efficient in symptomatic relief with beneficial effects on cognitive, functional and behavioral symptoms [23].
NMDAR antagonists that target various sites of this receptor have been tested to counteract excitotoxicity. Uncompetitive NMDAR antagonists target the ion channel pore thus reducing the calcium entry into postsynaptic neurons. Only one of them, namely memantine, reached the approval status in moderate to severe AD. This molecule is however of limited benefit in most AD patients, because it has only modest symptomatic effects and further has shown no significant effects in mild Alzheimer's disease [24,25]. Furthermore many other NMDAR antagonists have failed in advanced clinical trials for several neurodegenerative disorders [21,26,27]. Another approach in limiting excitotoxicity consists in inhibiting the presynaptic release of glutamate.
WO2009/133128, WO2009/133141, WO2009/133142, WO2011/054759, and WO2012/117076 disclose drug combinations suitable for use in the treatment of AD. WO2012/117076 particularly discloses the therapeutic efficacy of baclofen-acamprosate combination in AD, including for the protection of glutamate toxicity and/or Abeta toxicity. U.S. Pat. No. 9,144,558, which derives from WO2012/117076, also discloses the use of a combination of baclofen and acamprosate for the treatment of AD. U.S. Pat. No. 9,144,558 also describes a list of compounds that could be further combined with baclofen and acamprosate. U.S. Pat. No. 9,144,558, however, does not teach that a combination of idalopirdine, baclofen and acamprosate may display an effect at suboptimal doses of idalopirdine, let alone that it would result in a synergistic effect.
Idalopirdine is a selective 5-HT6 receptor antagonist that has shown some efficacy in treating AD and has been under clinical trial as an add-on therapy for donepezil [55, NCT02079246].
Despite active research in this area, there is still a need for alternative or improved efficient therapies for Alzheimer's disease and Alzheimer's related disorders.